Methionine deficiency causes spermatogonial apoptosis via oxidative stress and DNA damage response pathway

Methionine serves as an essential amino acid regulating de novo protein synthesis and redox homeostasis. Previous studies have established adverse impacts of methionine restriction and deprivation on semen quality, but effects on early spermatogenesis remain poorly characterized. In this study, a methionine dietary model (0.86%, 0.17%, 0%) was used to investigate the role of methionine in early spermatogenesis. The results indicated that methionine deprivation caused spermatogenesis defects by inhibiting spermatogonial proliferation and increasing apoptosis. Further studies showed that methionine deprivation downregulated mitochondrial function-related genes (Gpx4, Fis1 and Gstm1), but upregulated ISR- (Atf4, Chac1 and Ddit3) and DNA damage response-related genes (Cdkn1a, Chek2 and Atm). Meanwhile, methionine deprivation caused mitochondrial dysfunction characterized by mitochondrial membrane potential depolarization, ROS accumulation, and MitoSOX accumulation. Methionine deprivation also caused an obvious increase in DNA damage response proteins (γH2AX, p-CHK2 and p-p53) and pro-apoptotic proteins (PUMA, BAX and c-PARP1), but suppressed anti-apoptotic protein BCL2. Furthermore, NAC effectively reversed the proliferation deficiency of GC-1 cells caused by methionine deprivation. Collectively, these findings suggest that methionine deprivation triggers ISR activation, which subsequently induces spermatogonial apoptosis via oxidative stress and the CHK2-p53/p21 signaling cascade. This study highlights the critical role of methionine in early spermatogenesis, provides mechanistic insights for optimizing dietary interventions and addresses related reproductive disorders.

• Publication year

  2025

• Venue

  Biological Research

• Publication date

  2025-11-12

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1186/s40659-025-00652-zPMID 41219782PMCID 12606962
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The role of p53 in male infertility

  2024cited by this paper
• Gene expression programs in mammalian spermatogenesis.

  2024cited by this paper
• Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions

  2024cited by this paper
• Development of a novel testis-on-a-chip that demonstrates reciprocal crosstalk between Sertoli and Leydig cells in testicular tissue

  2024cited by this paper
• Radiotherapy and Testicular Function: A Comprehensive Review of the Radiation-Induced Effects with an Emphasis on Spermatogenesis

  2024cited by this paper
• Separation of reproductive decline from lifespan extension during methionine restriction

  2024cited by this paper
• Oocyte‐specific deletion of eukaryotic translation initiation factor 5 causes apoptosis of mouse oocytes within the early‐growing follicles by mitochondrial fission defect‐reactive oxygen species‐DNA damage

  2024cited by this paper
• Biological properties of vitamin B12.

  2024cited by this paper
• CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers

  2024cited by this paper
• Sweet Taste Receptor T1R3 Expressed in Leydig Cells Is Closely Related to Homeostasis of the Steroid Hormone Metabolism Profile.

  2023cited by this paper
• eIF3d controls the persistent integrated stress response.

  2023cited by this paper
• Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response

  2023cited by this paper
• Amino acid deprivation induces TXNIP expression by NRF2 downregulation

  2023cited by this paper
• Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila

  2023cited by this paper
• Effects of Dietary Methionine Restriction on Cognition in Mice

  2023cited by this paper
• The molecular basis of translation initiation and its regulation in eukaryotes

  2023cited by this paper
• Glutathione and Glutathione-dependent Enzymes: From Biochemistry to Gerontology and Successful Aging.

  2023cited by this paper
• Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade

  2023cited by this paper
• Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity.

  2023cited by this paper
• Drosophila as a diet discovery tool for treating amino acid disorders.

  2022cited by this paper
• A male germ-cell-specific ribosome controls male fertility.

  2022cited by this paper
• Methionine restriction - Association with redox homeostasis and implications on aging and diseases

  2022cited by this paper
• Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

  2022cited by this paper
• Activation and execution of the hepatic integrated stress response by dietary essential amino acid deprivation is amino acid specific

  2022cited by this paper
• The Origins, Evolution, and Future of Dietary Methionine Restriction.

  2022cited by this paper
• FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice

  2022cited by this paper
• Overexpression of PD‐L1 causes germ cells to slough from mouse seminiferous tubules via the PD‐L1/PD‐L1 interaction

  2022cited by this paper
• Imbalanced GSH/ROS and sequential cell death

  2021cited by this paper
• Should we be measuring DNA damage in human spermatozoa? New light on an old question.

  2021cited by this paper
• Sensing and Signaling of Methionine Metabolism

  2021cited by this paper
• The acute transcriptional responses to dietary methionine restriction are triggered by inhibition of ternary complex formation and linked to Erk1/2, mTOR, and ATF4

  2021cited by this paper
• Differences in cell death in methionine versus cysteine depletion

  2021cited by this paper
• Amino Acid Depletion Therapies: Starving Cancer Cells to Death.

  2021cited by this paper
• Baking of methionine-choline deficient diet aggravates testis injury in mice.

  2021cited by this paper
• A new translation and reader's guide to the first detailed description of the first wave of spermatogenesis in the mouse

  2021cited by this paper
• Sertoli cells as key drivers of testis function.

  2021cited by this paper
• The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells.

  2021cited by this paper
• Proteostasis regulated by testis-specific ribosomal protein RPL39L maintains mouse spermatogenesis

  2021cited by this paper
• Amino acid deprivation induces AKT activation by inducing GCN2/ATF4/REDD1 axis

  2021cited by this paper
• Essential roles of interstitial cells in testicular development and function

  2020cited by this paper
• Reactive oxygen species-evoked genotoxic stress mediates arsenic-induced suppression of male germ cell proliferation and decline in sperm quality.

  2020cited by this paper
• Male infertility due to testicular disorders.

  2020cited by this paper
• The integrated stress response: From mechanism to disease

  2020cited by this paper
• Redistribution of EC‐SOD resolves bleomycin‐induced inflammation via increased apoptosis of recruited alveolar macrophages

  2019cited by this paper
• Physiological and Molecular Mechanisms of Methionine Restriction

  2018cited by this paper
• Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine

  2018cited by this paper
• Methionine in Proteins: It’s Not Just for Protein Initiation Anymore

  2018cited by this paper
• The integrated stress response

  2016cited by this paper
• Role of GCN2-Independent Signaling Through a Noncanonical PERK/NRF2 Pathway in the Physiological Responses to Dietary Methionine Restriction

  2016cited by this paper
• Mechanistic basis of hypermethioninemia

  2016cited by this paper
• A 4-Week Toxicity Study of Methionine in Male Rats

  2015cited by this paper
• Mammalian proapoptotic factor ChaC1 and its homologues function as γ‐glutamyl cyclotransferases acting specifically on glutathione

  2012cited by this paper
• Protecting the heritable genome: DNA damage response mechanisms in spermatogonial stem cells.

  2011cited by this paper
• Methionine deprivation regulates the S6K1 pathway and protein synthesis in avian QM7 myoblasts without activating the GCN2/eIF2 alpha cascade.

  2010cited by this paper
• Prolonged, but not acute, glutathione depletion promotes Fas‐mediated mitochondrial permeability transition and apoptosis in mice

  2001cited by this paper
• Effects of the transmethylation inhibitor S-adenosyl-homocysteine and of the methyl donor S-adenosyl-methionine on rat Leydig cell function in vitro.

  1987cited by this paper
• Effect of excess dietary methionine on rat pregnancy: influence on ovarian delta5-3beta-hydroxysteroid dehydrogenase activity.

  1977cited by this paper

• No citing papers are available for this paper.